White blood cells can protect the body against various microbial infections as well as diseases such as cancer. However, when white blood cells adhere to endothelial cells on the lumenal site of blood vessels, migrate to body tissues and accumulate there, they often cause damage, swelling, pain, and inflammation. For example, rheumatoid arthritis occurs when white blood cells enter the joints and attack the tissues. It is believed that several molecules on white blood cells recognize their receptors on the surface of the endothelial cell, allowing them to migrate through the blood vessel wall to the site of inflammation. These cell surface molecules on leukocytes and endothelial cells are called cell adhesion receptors. It is believed that if the recognition between these cellular receptors can be blocked, the inflammatory response can be reduced or eliminated.
Different adhesion receptors are presented on the endothelial cell surface at different times and may be recognized by different types of white blood cells. It is possible that two or more receptors may work together to perform this task. Several molecules are already known to act in this fashion.
Many endothelial cell receptors appear to belong to one of two structural supergene families. The Ig super-family includes ICAM-1 (CD54) and VCAM-1 because of their structural similarity to antibodies. Members of this family interact with receptors on white blood cells known as integrins (CD11/CD18, and VLA-4). The other class, which includes ELAM-1 and GMP-140, are known as LEC-CAMS or selectins. It is believed that they interact with various oligosaccharides on CD15 molecule that is located on white blood cell surfaces. Another member of the LEC-CAM family is the homing receptor (Mel-14, gp90, and Leu-8) located on the surface of leukocytes and recognizes an unidentified molecule on the endothelial cell.
Accordingly, there is a need to interfere with the interaction between white blood cells and endothelial cells to prevent various disease states, for example, rheumatoid arthritis, atherosclerosis, acute and chronic inflammation, arthritis, adult respiratory distress system, autoimmune diseases, and certain cancers. The present inventors have identified several protein compounds that are effective in interfering with white blood cell adhesion to endothelial cells. Those compounds are discussed below.